Hypovolemic shock resulting from an acute loss of circulating blood volume is characterized by hypotension, tachycardia and oliguria. These parameters are used to assess the adequate efficacy of resuscitation fluids after trauma. However, they are insensitive to the existence of regional hypoperfusion, and conditions may appear “normal” even though occult tissue hypoxia may be present (Shoemaker et al., 1998). Using these traditional endpoints of resuscitation, hemorrhagic shock may appear to be 50-85% “compensated” although ongoing inadequate or impaired tissue perfusion can persist in different tissue localities (Porter and Ivatury, 1998). Suboptimal or inadequate resuscitation contributes to develop multiple organ failure and may ultimately result in death (Ivatury et al., 1996). Therefore there is significant interest in trying to identify more sensitive indicators of under-resuscitation and poor perfusion (Beilman et al., 1996; Powell et al., 1995; Sato et al., 1997; Zhang et al., 1996).
Skeletal muscle responds rapidly to acute blood loss and provides an easily accessible tissue site for monitoring the effects of hemorrhagic shock in experimental conditions (Cabrales et al., 2004, 2005; Kerger et al., 1996; Wettstein et al., 2004). In general these studies show that compensatory mechanisms such as vasoconstriction, activated during hemorrhage to maintain adequate tissue perfusion to vital organs, decrease blood flow in the microcirculation leading to impaired oxygen delivery and the generation of lactic acid via anaerobic glycolysis (Guyton 1996). Additionally, poor blood flow prevents the normal removal of carbon dioxide, which reacting with water forms high intracellular concentrations of carbonic acid (De Blasi et al., 1996; Guyton 1996; Rixen et al., 2002). The progressive increase of tissue acids and the concomitant reduction in bicarbonate lead to regional tissue acidosis, therefore monitoring skeletal muscle acid-base status should provide a sensitive means of assessing the severity of shock and the adequacy of resuscitation.
Accumulation of lactate tends to occur in conditions of oxygen depletion (ischemic hypoxia). Lactate is produced in skeletal muscle for glycolysis. Although skeletal muscle is the main producer of lactate in the body, lactate can also be taken up by skeletal muscle and used as a respiratory fuel. Lactate is a useful metabolic intermediate that can be exchanged between different cells within a given muscle, or exchanged between muscle and blood, and between muscle and other tissues (Aalkjier and Peng, 1997; Carsten 2001). The release and uptake of lactate is mediated mainly by monocarboxylate transporter. Lactate transport shows an obligatory 1:1 coupling between lactate and H+ fluxes, and is therefore of great importance for pH regulation, especially during oxygen depravation or increased muscle activity (Aalkjier and Peng, 1997; Carsten 2001). The involvement of lactate/H+ cotransport in pH regulation is important for interstitial pH homeostasis, which may have important regulatory consequences, since the interstitial H+ concentration may influence sensory nerve endings involved in the reflex regulation of blood flow and ventilation (Aalkjier and Peng, 1997; Carsten 2001).
Monitoring the microenvironment of skeletal muscle during shock is not a novel concept and previous investigators have demonstrated that changes in skeletal muscle pO2, pCO2, and pH levels occur rapidly after hemorrhage (Brantigan et al. 1974). However, monitoring tissue changes during shock and resuscitation is cumbersome and impractical. Optical techniques based on the use of low concentration pH-sensitive fluorescent dyes have been used successfully to measure pH (Moolenaar et al 1983), an in situ technology which should be well suited for analyzing tissue conditions during hemorrhage resuscitation to evaluate different fluids and procedures. This information is particularly relevant during evaluation of changes in oxygen delivery and release at the microcirculation using different plasma expanders, since pH affects the shape of the oxygen dissociation curve of hemoglobin via the Bohr effect. Tissue pH can be a powerful tool to easily establish a constitute index for aerobic and anaerobic metabolism of the tissue, specially on skeletal muscle where lactate and H+ fluxes regulate pH.
Endotoxemia leading to sepsis is managed according to the “VIP” principles, namely Ventilate, Infuse and Pump (Weil and Shubin, 1969) on the basis that: 1) it is essential to maintain adequate tissue oxygenation; 2) administration of fluid is required to treat hypotension and maintain tissue perfusion; and, 3) central blood pressure should be maintained to support tissue perfusion following fluid resuscitation. Treatment according to these principles (Vincent et al, 2002) addresses systemic conditions and not necessarily problems at the microscopic functional level, leading to uncertain results as shown by the high morbidity and mortality associated with severe sepsis (Alberti et al., 2003).
Analysis of septic shock in the microcirculation has been inconclusive in identifying functional impairments that must be remedied, in part because of the difficulty of studying exposed microvascular preparations for extended periods. This problem is circumvented using chamber window models which allow analysis of the microcirculation for several days, showing conditions at the onset of sepsis, the response to treatment modalities, while monitoring systemic parameters. Microvascular studies show that maintenance of functional capillary density (FCD) is more critical for insuring survival during hemorrhagic shock than maintaining tissue pO2 (Kerger et al., 1996). Decreased FCD follows capillary compression by tissue edema, endothelial swelling and plugging by leukocytes or red blood cell whose rigidity is increased due to endotoxemia (Nevière and Sibbald, 2000); however, FCD changes have not been extensively investigated in relation to sepsis.
Hdroxyethyl starch (HES) was found to maintain FCD but not NaCl (Hoffmann et al., 2002) in normotensive endotoxemia, and studies of capillary morphology show that microvascular surface area for O2 exchange in septic sheep may be increased with infused colloids (Morisaki et al., 1994). Endotoxemia causes tissue hypoxia (Anning et al. 1999, Sair et al. 1996), which is reversed by fluid resuscitation but not by increased inspired O2 (F1O2). Capillary O2 extraction in sepsis is increased due to stopped flow in the rat skeletal muscle, suggesting that maldistribution of microvascular blood flow mismatches O2 supply and demand (Ellis et al. 2002).
Maintenance or restoration of FCD should be important in the treatment of endotoxemia since the eradication of pathogens requires the delivery of antimicrobial agents through the circulation, an ineffectual process with decreased FCD.